The goal of this proposed research is to use the powerful tools of molecular genetics and gene knockout technology to study the consequence of the absence of each of the adult fast MYH isoforms independently on the phenotypes and composition of specific muscle fibers. The molecular basis of many skeletal muscle diseases and abnormalities is unknown. The numerous components of the myofibril makes it necessary to target specific gene products in an attempt to document the specific molecule involved. Inherited genetic defects in MYH have been described for familial hypertrophic cardiomyopathy, and it is likely that genetic alterations may be responsible for skeletal muscle myopathies also. The genes for adult MYH fast isoforms IIa, IIb, and IId have been successfully inactivated in the mouse. The Specific Aims of this proposal are to 1) characterize the MRNA levels and protein composition of all MYH family members in targeted major muscles in each fast II MYH knockout, 2) determine the histology of major muscles by different staining techniques and by measuring fiber diameters, and 3) study the muscle physiology and the effect of exercise in the knockout mice in a collaborative effort. The analogy of the molecular and physiologic properties of the muscle fibers in these mice-to skeletal muscle abnormalities will be determined in an effort to establish the molecular basis of human muscle pathologies.